The tropomyosin receptor kinase (hereinafter abbreviated as “Trk”) family is classified as receptor tyrosine kinases and comprises TrkA which is a high-affinity receptor of nerve growth factor (hereinafter abbreviated as NGF), TrkB which is a high-affinity receptor of brain-derived neutrophic factor (BDNF) and neurotrophin (hereinafter abbreviated as NT)-4/5 and TrkC which is a high-affinity receptor of NT-3. All Trk receptors are highly expressed in nerve tissues and are involved in differentiation and maintenance of functions of nerve cells (see Non-Patent Document 1). Meanwhile it has been known that activation of TrkA in peripheral nerves by NGF initiates hyperalgesia (see Non-Patent Document 2) and based on clinical and non-clinical test results using anti-NGF antibodies and non-clinical test results using low-molecular weight Trk inhibitors, involvement of TrkA has been reported in nociceptive pain of osteoarthritis, chronic low back pain, rheumatoid arthritis, bone fracture, interstitial cystitis and chronic pancreatitis, neuropathic pain as well as cancer pain combining both types of pain described above (see Non-Patent Document 3 to 10). Moreover, Trk receptors are expressed on cancer cells such as neuroblastoma, prostate cancer and pancreatic cancer, inflammatory cells such as mast cells and eosinophils, immunocompetent cells such as T cells and B cells and keratinocytes and are reported to be potentially involved in proliferation, migration and metastasis of cancer cells, inflammatory diseases such as ulcerative colitis and Crohn's disease, allergic diseases such as asthma, rhinitis and atopic dermatitis and other diseases such as psoriasis (see Non-Patent Document 11 to 15). Therefore compounds having Trk-inhibiting activity may be applied to therapy of nociceptive pain, neuropathic pain and pain combining both types of pain, cancer, inflammatory diseases, allergic diseases and psoriasis.
Accordingly it is expected that development of Trk-inhibiting agents may provide novel types of prophylactic and/or therapeutic agents for pain and the like.
Meanwhile Patent Document 1 discloses a method for treating or preventing a disease in a human or other mammal regulated by tyrosine kinase, comprising administering, to a human or other mammal in need thereof, a compound of the following formula (Ia), a salt thereof, an isomer thereof or a prodrug of the compound.
The general formula (Ia) is as follows:

wherein Aa is selected from the group consisting of the following (i) to (iii) and the like;
(i) phenyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen and the like;
(ii) naphthyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen and the like;
(iii) a 5- to 6-membered monocyclic heteroaryl group, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen and the like and having 1 to 3 heteroatoms independently selected from the group consisting of O, N and S;
Ba is selected from the group consisting of the following (i) to (iii) and the like;
(i) phenyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of —La-Ma, a C1-C5 linear or branched alkyl, a halogen and the like;
(ii) naphthyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of —La-Ma, a C1-C5 linear or branched alkyl, a halogen and the like;
(iii) a 5- to 6-membered monocyclic heteroaryl group, optionally substituted with 1 to 3 substituents independently selected from the group consisting of —La-Ma, a C1-C5 linear or branched alkyl, a halogen and the like and having 1 to 3 heteroatoms independently selected from the group consisting of O, N and S;
La is selected from the group consisting of —(CH2)ma—O— (CH2)la—, —(CH2)ma—C(O)—(CH2)la— and the like, wherein the variables ma and la are integers independently selected from 0 to 4;
Ma is selected from the group consisting of the following (i) to (iii) and the like;
(i) phenyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen and the like;
(ii) naphthyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen and the like;
(iii) a 5- to 6-membered monocyclic heteroaryl group, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ra1, ORa1, a halogen and the like and having 1 to 3 heteroatoms independently selected from the group consisting of O, N and S;
wherein Ra1 is independently selected from the group consisting of (a) a hydrogen, (b) a C1-C6 alkyl, (c) phenyl, (d) a 5- to 6-membered monocyclic heteroaryl or a 8- to 10-membered bicyclic heteroaryl both having 1 to 4 heteroatoms selected from the group consisting of O, N and S, (e) a C1-C3 alkyl-phenyl and (f) an alkyl-heteroaryl having 1 to 4 heteroatoms selected from the group consisting of O, N and S; Ra1 is, when it is not a hydrogen, optionally substituted with 1 to 3 substituents independently selected from the group consisting of a C1-C5 linear, branched or cyclic alkyl, a C1-C3 alkoxy, hydroxy, amino, a C1-C3 alkylamino, a C2-C6 dialkylamino, a halogen, cyano and nitro (the definitions of the groups are partially abstracted).
Patent Document 1 discloses that the compound therein inhibits KDR and thereby is used for a method of treatment of diseases mediated by VEGF induced signal transduction pathways in a human or other mammal, particularly retinopathy or retinopathy of prematurity. However, it is not disclosed or suggested that the compound disclosed therein has Trk-inhibiting activity and Patent Document 1 does not specifically disclose the present compound.
Patent Document 2 discloses that a compound represented by the general formula (Ib):

wherein:
Qb1 and Qb2 are individually and independently selected from the group consisting of N and CH, and at least one of Qb1 and Qb2 is N;
each Db is individually selected from the group consisting of C, CH, C—Rb20, N—Zb3, N, O and S, such that the resultant ring is taken from the group consisting of pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxazolyl and thiadiazolyl;
Eb is selected from the group consisting of phenyl, pyridyl and pyrimidinyl;
Xb2 is selected from the group consisting of —O—, — S(CH2)nb—, —N(Rb3) (CH2)nb— and —(CH2)pb—;
when only one of Qb1 and Qb2 is N, the ring Ab is selected from the group consisting of cyclopentyl, cyclohexyl, Gb1, Gb2, Gb3 and Gb4 optionally substituted with the substituent Zb2, Rb2 and the like;
Gb1 is a heteroaryl selected from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl and the like;
Gb4 is selected from the group consisting of phenyl, naphthyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl and pyrimidinyl;
Zb2 is selected from the group consisting of aryl, a C1-C6 alkyl, a C3-C8 cycloalkyl, a branched C3-C7 alkyl and the like;
Rb2 is selected from the group consisting of a substituted aryl, substituted Gb1, substituted Gb4, a halogen and the like (the definitions of the groups are partially abstracted), a stereoisomer, regioisomer and tautomer of the compound have Abl-inhibiting activity, c-Met-inhibiting activity, b-Raf-inhibiting activity and c-Kit-inhibiting activity. However, it is not disclosed or suggested that the compounds have Trk-inhibiting activity. In addition, Patent Document 2 does not disclose the present compound.
Patent Document 3 discloses that a compound represented by the general formula (Ic):

wherein:
each Dc is individually selected from the group consisting of C, CH, C—Rc20, N—Zc3 and N, such that the resultant ring is pyrazole;
Ec is selected from the group consisting of phenyl, pyridyl and pyrimidinyl;
Xc is selected from the group consisting of —O—, — S(CH2)nc—, —N(Rc3)(CH2)nc— and —(CH2)pc—;
Ac is a ring system selected from the group consisting of phenyl, naphthyl, cyclopentyl, cyclohexyl, Gc1, Gc2 and Gc3, optionally substituted with the substituent Zc2, Rc2 and the like;
Gc1 is a heteroaryl selected from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl and the like;
Gc2 is a fused bicyclic heteroaryl selected from the group consisting of indolyl, indolinyl, isoindolyl and the like;
Gc3 is a heterocyclyl selected from the group consisting of oxetanyl, tetrahydrofuranyl, pyrrolidinyl and the like;
Zc2 is selected from the group consisting of an aryl, a C1-C6 alkyl, a C3-C8 cycloalkyl, a branched C3-C7 alkyl and the like;
Rc2 is selected from the group consisting of a C1-C6 alkyl, a branched C3-C8 alkyl, a halogen and the like (the definitions of the groups are partially abstracted), a stereoisomer, regioisomer and tautomer of the compound have Abl-inhibiting activity, c-Met-inhibiting activity and c-Kit-inhibiting activity. However, it is not disclosed or suggested that the compounds have Trk-inhibiting activity. In addition, Patent Document 3 does not disclose the present compound.
Patent Document 1: WO 2003/068228
Patent Document 2: WO 2008/131276
Patent Document 3: WO 2008/131227
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